CA2447673A1 - Process for the isolation of crystalline imipenem - Google Patents
Process for the isolation of crystalline imipenem Download PDFInfo
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- CA2447673A1 CA2447673A1 CA002447673A CA2447673A CA2447673A1 CA 2447673 A1 CA2447673 A1 CA 2447673A1 CA 002447673 A CA002447673 A CA 002447673A CA 2447673 A CA2447673 A CA 2447673A CA 2447673 A1 CA2447673 A1 CA 2447673A1
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- Prior art keywords
- organic solvent
- water
- imipenem
- mixture
- solution
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
Abstract
The present invention relates to a cost effective and industrially advantageous process for the preparation of imipenem of high purity.
Description
PROCESS FOR THE ISOLATION OF CRYSTALLINE IMIPENEM
FIELD OF THE INVENTION
The present invention relates to a cost effective and industrially advantageous process for the preparation of imipenem of high purity.
BACKGROUND OF THE INVENTION
Imipenem monohydrate is the N-formimidoyl derivative of thienamycin, and has the structural Formula I.
OH
S~NH~ NH
N~ .H20 O COZH
FORMULA I
It is the first clinically available member of a new class of ~3-lactam antibiotics that possess the carbapenem ring system. Imipenem exhibits an extremely broad spectrum of activity against gram-positive and gram-negative aerobic and anaerobic species, which is partly due to its high stability in the presence of ~3-lactamases.
Imipenem was first disclosed in U.S. Patent No. 4,194,047 and was obtained by lyophilization technique. The product obtained by lyophilization is found to be largely amorphous and stated to be thermodynamically unstable.
The process also involves an initial purification through column chromatography using hydrophobic resins.
A thermodynamically stable crystalline monohydrate form of imipenem is disclosed in U.S. Patent No. 4,260,543 which is obtained by crystallization of a lyophilized sample of imipenem. However, this process is not satisfactory on a commercial scale as it requires isolation of the product by column chromatography, lyophilization, followed by crystallization. Moreover, CONFIRMATION COPY
the prolonged process for isolation of the final product leads to degradation of imipenem, thus affecting the purity of the product.
U.S. Patent No. 4,292,436 discloses crystalline imipenem by purifying the crude product by column chromatography. Further, Crocker et al, have reported in J. Pharm. Sci. 84, 226 (1995) that changes in lyophilization parameters result in varying degrees of crystallinity in the isolated imipenem samples. A variant method for preparing imipenem having a high degree of crystallinity by freeze crystallization process has been reported by Connolly et. al. in J. Pharm. Sci, 85, 174(1996). However, these processes are tedious, cumbersome and unsuitable for industrial use.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a simple, practical and efficient method for the preparation of crystalline imipenem monohydrate which is thermally stable, has a uniform degree of crystallinity and high purity.
The present invention relates to a process for the isolation of pure crystalline imipenem monohydrate from a solution containing imipenem. The process does not use capital intensive techniques of lyophilization or freeze crystallization as well as the time consuming purification process of column chromatography using expensive hydrophobic resins. The present invention thus fulfills the need for a process which is convenient to operate on a commercial scale.
Accordingly, the present invention provides a process for the isolation of pure crystalline imipenem monohydrate of Formula I, OH
S~NH~ NH
/ N~ .H2o FORMULA I
FIELD OF THE INVENTION
The present invention relates to a cost effective and industrially advantageous process for the preparation of imipenem of high purity.
BACKGROUND OF THE INVENTION
Imipenem monohydrate is the N-formimidoyl derivative of thienamycin, and has the structural Formula I.
OH
S~NH~ NH
N~ .H20 O COZH
FORMULA I
It is the first clinically available member of a new class of ~3-lactam antibiotics that possess the carbapenem ring system. Imipenem exhibits an extremely broad spectrum of activity against gram-positive and gram-negative aerobic and anaerobic species, which is partly due to its high stability in the presence of ~3-lactamases.
Imipenem was first disclosed in U.S. Patent No. 4,194,047 and was obtained by lyophilization technique. The product obtained by lyophilization is found to be largely amorphous and stated to be thermodynamically unstable.
The process also involves an initial purification through column chromatography using hydrophobic resins.
A thermodynamically stable crystalline monohydrate form of imipenem is disclosed in U.S. Patent No. 4,260,543 which is obtained by crystallization of a lyophilized sample of imipenem. However, this process is not satisfactory on a commercial scale as it requires isolation of the product by column chromatography, lyophilization, followed by crystallization. Moreover, CONFIRMATION COPY
the prolonged process for isolation of the final product leads to degradation of imipenem, thus affecting the purity of the product.
U.S. Patent No. 4,292,436 discloses crystalline imipenem by purifying the crude product by column chromatography. Further, Crocker et al, have reported in J. Pharm. Sci. 84, 226 (1995) that changes in lyophilization parameters result in varying degrees of crystallinity in the isolated imipenem samples. A variant method for preparing imipenem having a high degree of crystallinity by freeze crystallization process has been reported by Connolly et. al. in J. Pharm. Sci, 85, 174(1996). However, these processes are tedious, cumbersome and unsuitable for industrial use.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a simple, practical and efficient method for the preparation of crystalline imipenem monohydrate which is thermally stable, has a uniform degree of crystallinity and high purity.
The present invention relates to a process for the isolation of pure crystalline imipenem monohydrate from a solution containing imipenem. The process does not use capital intensive techniques of lyophilization or freeze crystallization as well as the time consuming purification process of column chromatography using expensive hydrophobic resins. The present invention thus fulfills the need for a process which is convenient to operate on a commercial scale.
Accordingly, the present invention provides a process for the isolation of pure crystalline imipenem monohydrate of Formula I, OH
S~NH~ NH
/ N~ .H2o FORMULA I
which comprises crystallizing imipenem monohydrate from a solution thereof which contains an organic, aqueous solvent or a mixture thereof, without using lyophilization, freeze drying or chromatographic techniques.
The solvent system from which the product may be crystallized will desirably be selected from organic solvents which are water-miscible organic solvents, either alone or in admixture with water.
Examples of such water-miscible organic solvents include lower alcohols such as methanol, ethanol, propanol and isopropanol; ketones such as acetone; glycol ethers such as monoethylene glycol; amides such as N, N-dimethylformamide, N, N-dimethylacetamide; lactams such as N-methylpyrrolidone and cyclic ethers such as tetrahydrofuran, dioxane, or mixtures) thereof.
The crystallization step will desirably be carried out at low temperatures, for example at about 0°-C to about 15°-C, and the concentration of imipenem in the solution from which crystallization will occur will generally be adjusted e.g. by evaporation of the solvent or by dilution so as to be neither too dilute nor too concentrated.
The crystallization may comprise the last stage or stages of a reaction in which the imipenem is formed. The reaction in which the imipenem is formed may be carried out by following any of the synthetic routes described in the prior art viz. U.S. Patent Nos. 4,194,047; 4,292,436; 4,374,772; or 4,894,450 and are incorporated herein by reference, but will preferably be carried out in the manner described in the patent application filed concurrently herewith and exemplified as example 1 in this patent application.
Before carrying out the process of crystallization, the solution containing imipenem may be washed with an organic solvent having limited miscibility in water to remove organic impurities.
Also, pH of the solution of imipenem is adjusted, if required, to about 7 to 8 before washings to facilitate removal of impurities.
In the meaning of the present invention, the term "limited miscibility"
shall also include water-immiscible solvents. Examples of such organic solvents include carboxylic acid esters such as ethyl acetate, higher alkyl ketones such as methylisobutyl ketone, chlorinated hydrocarbons such as dichloromethane, ethers such as diethyl ether, aromatic hydrocarbons such as toluene, and mixtures) thereof.
DETAILED DESCRIPTION OF THE INVENTION
In the following section preferred embodiments are described by way of examples to illustrate the process of the invention. However, these are not intended in any way to limit the scope of the present invention.
PREPARATION OF IMIPENEM
Example 1 Step (a) - Preparation of enol phosphate intermediate p-Nitrobenzyl (3R, 5R, 6S)-2oxo-6-[(1 R)-1-hydroxyethyl)] carbapenem-3-carboxylate (30g) was dissolved in a mixture of N, N-dimethylacetamide (300m1) and dichloromethane (150m1). The solution was cooled to -55°-C
and dimethylaminopyridine (0.17g) was added followed by diisopropylethylamine (26.7g). The mixture was stirred for 5 minutes at about -55°-C and then a solution of diphenylchlorophosphate (25.4g) in dichloromethane (30m1) was added dropwise at -55 to -45°C. The reaction was stirred further for 30 minutes to obtain the enol phosphate ester.
Step (b) - Preparation of thienamycin ester The reaction mixture from step (a) was further cooled to -70 to -75°-C
and a solution of 2-aminoethanethiol hydrochloride (12g) in N, N-dimethylacetamide (60m1) was added in 10 minutes at -75 to -60°-C. The reaction mixture was stirred for another 60 minutes to produce p-nitrobenzyl ester of thienamycin.
Step (c) - Preparation of p-nitrobenzyl ester of imipenem To the above reaction mixture from step (b), was added diisopropylethylamine (16.0g) and benzyl formimidate hydrochloride (20.0g) at -50 to -55°-C. The reaction was allowed to continue for about one and a half hour at the same temperature. The temperature was then raised to -20°-C
and the reaction mixture was stirred for 20-30 minutes at this temperature to obtain a clear solution of imipenem ester.
Step (d) - Preparation of imipenem The above clear solution obtained from step (c) was poured into a mixture of water (300m1), isopropanol (150m1) and N-methylmorpholine (26g) maintained at 5-10°-C and the pH of the solution adjusted to 7.0 to 7.5. The solution was hydrogenated at 3-4 kg pressure for 2.5 hours at 10-25°-C
over palladium-charcoal. The mixture was filtered and assayed for imipenem (80%, as determined by HPLC).
ISOLATION OF CRYSTALLINE IMIPENEM MONOHYDRATE
Example 2 The reaction mixture containing imipenem obtained at step (d ) Example 1 was stirred with dichloromethane (900m1) maintaining pH between 7.0 to 8.0 and the aqueous layer separated. The aqueous portion was degassed to remove dichloromethane and given activated carbon treatment.
The filtered aqueous solution was mixed with isopropanol (400m1) and stirred at 5-10°-C for 3 hours . The crystalline product so obtained was filtered, washed with isopropropanol followed by acetone and dried at 35-40°-C
for 1 hour to obtain crystalline imipenem monohydrate (9.0g, purity 99% by HPLC).
The solvent system from which the product may be crystallized will desirably be selected from organic solvents which are water-miscible organic solvents, either alone or in admixture with water.
Examples of such water-miscible organic solvents include lower alcohols such as methanol, ethanol, propanol and isopropanol; ketones such as acetone; glycol ethers such as monoethylene glycol; amides such as N, N-dimethylformamide, N, N-dimethylacetamide; lactams such as N-methylpyrrolidone and cyclic ethers such as tetrahydrofuran, dioxane, or mixtures) thereof.
The crystallization step will desirably be carried out at low temperatures, for example at about 0°-C to about 15°-C, and the concentration of imipenem in the solution from which crystallization will occur will generally be adjusted e.g. by evaporation of the solvent or by dilution so as to be neither too dilute nor too concentrated.
The crystallization may comprise the last stage or stages of a reaction in which the imipenem is formed. The reaction in which the imipenem is formed may be carried out by following any of the synthetic routes described in the prior art viz. U.S. Patent Nos. 4,194,047; 4,292,436; 4,374,772; or 4,894,450 and are incorporated herein by reference, but will preferably be carried out in the manner described in the patent application filed concurrently herewith and exemplified as example 1 in this patent application.
Before carrying out the process of crystallization, the solution containing imipenem may be washed with an organic solvent having limited miscibility in water to remove organic impurities.
Also, pH of the solution of imipenem is adjusted, if required, to about 7 to 8 before washings to facilitate removal of impurities.
In the meaning of the present invention, the term "limited miscibility"
shall also include water-immiscible solvents. Examples of such organic solvents include carboxylic acid esters such as ethyl acetate, higher alkyl ketones such as methylisobutyl ketone, chlorinated hydrocarbons such as dichloromethane, ethers such as diethyl ether, aromatic hydrocarbons such as toluene, and mixtures) thereof.
DETAILED DESCRIPTION OF THE INVENTION
In the following section preferred embodiments are described by way of examples to illustrate the process of the invention. However, these are not intended in any way to limit the scope of the present invention.
PREPARATION OF IMIPENEM
Example 1 Step (a) - Preparation of enol phosphate intermediate p-Nitrobenzyl (3R, 5R, 6S)-2oxo-6-[(1 R)-1-hydroxyethyl)] carbapenem-3-carboxylate (30g) was dissolved in a mixture of N, N-dimethylacetamide (300m1) and dichloromethane (150m1). The solution was cooled to -55°-C
and dimethylaminopyridine (0.17g) was added followed by diisopropylethylamine (26.7g). The mixture was stirred for 5 minutes at about -55°-C and then a solution of diphenylchlorophosphate (25.4g) in dichloromethane (30m1) was added dropwise at -55 to -45°C. The reaction was stirred further for 30 minutes to obtain the enol phosphate ester.
Step (b) - Preparation of thienamycin ester The reaction mixture from step (a) was further cooled to -70 to -75°-C
and a solution of 2-aminoethanethiol hydrochloride (12g) in N, N-dimethylacetamide (60m1) was added in 10 minutes at -75 to -60°-C. The reaction mixture was stirred for another 60 minutes to produce p-nitrobenzyl ester of thienamycin.
Step (c) - Preparation of p-nitrobenzyl ester of imipenem To the above reaction mixture from step (b), was added diisopropylethylamine (16.0g) and benzyl formimidate hydrochloride (20.0g) at -50 to -55°-C. The reaction was allowed to continue for about one and a half hour at the same temperature. The temperature was then raised to -20°-C
and the reaction mixture was stirred for 20-30 minutes at this temperature to obtain a clear solution of imipenem ester.
Step (d) - Preparation of imipenem The above clear solution obtained from step (c) was poured into a mixture of water (300m1), isopropanol (150m1) and N-methylmorpholine (26g) maintained at 5-10°-C and the pH of the solution adjusted to 7.0 to 7.5. The solution was hydrogenated at 3-4 kg pressure for 2.5 hours at 10-25°-C
over palladium-charcoal. The mixture was filtered and assayed for imipenem (80%, as determined by HPLC).
ISOLATION OF CRYSTALLINE IMIPENEM MONOHYDRATE
Example 2 The reaction mixture containing imipenem obtained at step (d ) Example 1 was stirred with dichloromethane (900m1) maintaining pH between 7.0 to 8.0 and the aqueous layer separated. The aqueous portion was degassed to remove dichloromethane and given activated carbon treatment.
The filtered aqueous solution was mixed with isopropanol (400m1) and stirred at 5-10°-C for 3 hours . The crystalline product so obtained was filtered, washed with isopropropanol followed by acetone and dried at 35-40°-C
for 1 hour to obtain crystalline imipenem monohydrate (9.0g, purity 99% by HPLC).
Example 3 The process of Example 2 was repeated using acetone (400m1) instead of isopropanol during crystallization. Crystalline imipenem monohydrate (8.0g) was obtained in 99% purity (by HPLC).
Example 4 The aqueous portion obtained as in Example 2 was concentrated to 200m1. The aqueous solution so obtained was given carbon treatment at 5-10°-C and the filtered solution was stirred with acetone (400m1) at 5-10°-C for 3 hours to obtain crystalline imipenem monohydrate after filtration and drying (12.0g, purity 98 - 99% by HPLC).
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 4 The aqueous portion obtained as in Example 2 was concentrated to 200m1. The aqueous solution so obtained was given carbon treatment at 5-10°-C and the filtered solution was stirred with acetone (400m1) at 5-10°-C for 3 hours to obtain crystalline imipenem monohydrate after filtration and drying (12.0g, purity 98 - 99% by HPLC).
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Claims (13)
1. A process for the isolation of pure crystalline imipenem monohydrate of Formula I, which comprises crystallizing imipenem monohydrate from a solution thereof which contains an organic solvent, aqueous solvent, or a mixture thereof, without using lyophilization, freeze drying or chromatographic techniques.
2. The process of claim 1 wherein the organic solvent comprises a water-miscible organic solvent.
3. The process of claim 1 wherein the solution comprises a water-miscible organic solvent in admixture with water.
4. The process of claim 2 wherein the water-miscible organic solvent comprises a lower alcohol, ketone, glycol ether, amide, lactam, cyclic ether, or a mixture thereof.
5. The process of claim 4 wherein said water-miscible organic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, acetone, monoethylene glycol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dioxane and mixture(s) thereof.
6. The process of claim 1 wherein the crystallization is carried out at a low temperature.
7. The process of claim 7 wherein the temperature is from about 0°C to about 15°C.
8. The process of claim 1 wherein the solution containing imipenem is obtained directly from a reaction mixture.
9. The process of claim 1 wherein the solution containing imipenem is washed with an organic solvent having limited miscibility in water before crystallization.
10. The process of claim 9 wherein the organic solvent having limited miscibility in water includes water-immiscible solvents.
11. The process of claim 9 wherein the organic solvent having limited miscibility in water comprises a carboxylic acid ester, higher alkyl ketone, chlorinated hydrocarbon, ether, aromatic hydrocarbon, or a mixture thereof.
12. The process of claim 11 wherein said organic solvent is selected from the group consisting of ethyl acetate, methylisobutyl ketone, dichloromethane, diethyl ether, toluene and mixture(s) thereof.
13. The process of claim 9 wherein the pH of the solution is adjusted to about 7 to 8 before carrying out the washing.
_g_
_g_
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN595/DEL/01 | 2001-05-18 | ||
IN595DE2001 | 2001-05-18 | ||
PCT/IB2002/001718 WO2002094773A2 (en) | 2001-05-18 | 2002-05-20 | Process for the isolation of crystalline imipenem |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2447673A1 true CA2447673A1 (en) | 2002-11-28 |
Family
ID=11097062
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002447673A Abandoned CA2447673A1 (en) | 2001-05-18 | 2002-05-20 | Process for the isolation of crystalline imipenem |
Country Status (17)
Country | Link |
---|---|
US (1) | US7241885B2 (en) |
EP (1) | EP1395588A4 (en) |
JP (1) | JP2005514323A (en) |
KR (1) | KR20040010649A (en) |
CN (1) | CN1522255A (en) |
AR (1) | AR036018A1 (en) |
BR (1) | BR0209844A (en) |
CA (1) | CA2447673A1 (en) |
CZ (1) | CZ20033351A3 (en) |
HU (1) | HUP0501093A2 (en) |
MX (1) | MXPA03010548A (en) |
NO (1) | NO20035137D0 (en) |
OA (1) | OA12608A (en) |
PL (1) | PL373527A1 (en) |
SK (1) | SK15092003A3 (en) |
WO (1) | WO2002094773A2 (en) |
ZA (1) | ZA200309288B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20040002973A (en) * | 2001-05-18 | 2004-01-07 | 랜박시 래보러터리스 리미티드 | Process for the preparation of imipenem |
WO2003016312A1 (en) * | 2001-08-13 | 2003-02-27 | Eisai Co., Ltd. | Process for preparation of carbapenem antibiotics |
MXPA04004604A (en) * | 2001-11-16 | 2004-09-10 | Ranbaxy Lab Ltd | Process for the preparation of crystalline imipenem. |
US8293924B2 (en) | 2007-10-08 | 2012-10-23 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of carbapenem antibiotic |
CN103524508B (en) * | 2013-09-02 | 2016-03-30 | 上海龙翔生物医药开发有限公司 | A kind of crystallization method of Imipenem monohydrate |
CN108623598A (en) * | 2018-05-21 | 2018-10-09 | 重庆天地药业有限责任公司 | A kind of preparation method of Imipenem intermediate and Imipenem |
CN113135916A (en) * | 2020-01-20 | 2021-07-20 | 鲁南制药集团股份有限公司 | Palladium removing method for imipenem preparation process |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4138433A (en) * | 1975-06-26 | 1979-02-06 | Hoechst Aktiengesellschaft | Process for preparing 1,2-oxa-phospholanes |
US4194047A (en) | 1975-11-21 | 1980-03-18 | Merck & Co., Inc. | Substituted N-methylene derivatives of thienamycin |
US4081455A (en) * | 1976-06-02 | 1978-03-28 | Pfizer Inc. | 6-Amino-2,2-dimethyl-3-cyanopenams |
US4260543A (en) | 1978-07-03 | 1981-04-07 | Merck & Co., Inc. | Crystalline N-formimidoyl thienamycin |
US4292436A (en) * | 1980-06-25 | 1981-09-29 | Merck & Co., Inc. | Process for the preparation of N-protected N-formimidoyl 2-aminoethanethiol |
US4374772A (en) | 1981-03-19 | 1983-02-22 | Merck & Co., Inc. | Process for the preparation of N-formimidoyl thienamycin and reagents therefor |
US4894450A (en) | 1987-05-11 | 1990-01-16 | Merck & Co., Inc. | Process for 2-(aminoalkylthio) carbapenems |
US5245069A (en) | 1992-10-27 | 1993-09-14 | Merck & Co., Inc. | Process for the preparation of bis(aryl)-phosphorohalidates |
IN191798B (en) | 2000-11-03 | 2004-01-03 | Ranbaxy Lab Ltd | |
MXPA04004604A (en) * | 2001-11-16 | 2004-09-10 | Ranbaxy Lab Ltd | Process for the preparation of crystalline imipenem. |
-
2002
- 2002-05-20 MX MXPA03010548A patent/MXPA03010548A/en unknown
- 2002-05-20 PL PL02373527A patent/PL373527A1/en not_active Application Discontinuation
- 2002-05-20 HU HU0501093A patent/HUP0501093A2/en unknown
- 2002-05-20 CZ CZ20033351A patent/CZ20033351A3/en unknown
- 2002-05-20 JP JP2002591446A patent/JP2005514323A/en not_active Withdrawn
- 2002-05-20 US US10/478,624 patent/US7241885B2/en not_active Expired - Fee Related
- 2002-05-20 EP EP02730574A patent/EP1395588A4/en active Pending
- 2002-05-20 AR ARP020101854A patent/AR036018A1/en not_active Application Discontinuation
- 2002-05-20 OA OA1200300302A patent/OA12608A/en unknown
- 2002-05-20 BR BR0209844-0A patent/BR0209844A/en not_active IP Right Cessation
- 2002-05-20 SK SK1509-2003A patent/SK15092003A3/en not_active Application Discontinuation
- 2002-05-20 KR KR10-2003-7015043A patent/KR20040010649A/en not_active Application Discontinuation
- 2002-05-20 CA CA002447673A patent/CA2447673A1/en not_active Abandoned
- 2002-05-20 CN CNA028131207A patent/CN1522255A/en active Pending
- 2002-05-20 WO PCT/IB2002/001718 patent/WO2002094773A2/en not_active Application Discontinuation
-
2003
- 2003-11-18 NO NO20035137A patent/NO20035137D0/en not_active Application Discontinuation
- 2003-11-28 ZA ZA200309288A patent/ZA200309288B/en unknown
Also Published As
Publication number | Publication date |
---|---|
MXPA03010548A (en) | 2004-05-27 |
JP2005514323A (en) | 2005-05-19 |
HUP0501093A2 (en) | 2006-03-28 |
WO2002094773A3 (en) | 2003-10-16 |
US7241885B2 (en) | 2007-07-10 |
EP1395588A4 (en) | 2004-09-15 |
KR20040010649A (en) | 2004-01-31 |
EP1395588A2 (en) | 2004-03-10 |
CZ20033351A3 (en) | 2007-12-27 |
NO20035137D0 (en) | 2003-11-18 |
ZA200309288B (en) | 2005-02-28 |
BR0209844A (en) | 2005-04-05 |
CN1522255A (en) | 2004-08-18 |
PL373527A1 (en) | 2005-09-05 |
AR036018A1 (en) | 2004-08-04 |
SK15092003A3 (en) | 2004-09-08 |
OA12608A (en) | 2006-06-08 |
WO2002094773A2 (en) | 2002-11-28 |
US20040242865A1 (en) | 2004-12-02 |
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